Bullock, Andrea J.

LBA4005 Background: To date, no phase 3 clinical trial has demonstrated an overall survival (OS) benefit in patients with locally advanced pancreatic adenocarcinoma (LA-PAC). TTFields are electric fields that disrupt cancer cell division. TTFields therapy is approved for glioblastoma, pleural mesothelioma, and metastatic non-small cell lung cancer. A phase 2 trial in PAC demonstrated the safety and preliminary efficacy of TTFields therapy with gemcitabine with or without nab-paclitaxel. We report final data from PANOVA-3 (NCT03377491), the largest global, phase 3, randomized, open-label trial in LA-PAC to date. Methods: Adult patients with newly diagnosed unresectable LA-PAC were randomized 1:1 to receive TTFields therapy (150 kHz) with gemcitabine/nab-paclitaxel (GnP) or GnP. The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), local PFS, objective response rate (ORR), and pain-free survival. Distant PFS (metastases beyond the pancreas and regional lymph nodes) was assessed post hoc. Survival data were compared using the Kaplan-Meier method and a log-rank test. Results: 571 patients were randomized. Baseline characteristics were generally well balanced between the study arms. OS was significantly longer with TTFields/GnP than with GnP (median 16.2 [95% CI: 15.0, 18.0] vs 14.2 months [95% CI: 12.8, 15.4]; HR 0.82 [95% CI: 0.68, 0.99], p=0.039). One-year survival rate was also significantly improved with TTFields/GnP vs GnP (68.1% [95% CI: 62.0-73.5] vs 60.2% [95% CI: 54.2-65.7], p=0.029). There was no significant difference in PFS or local PFS between arms. Pain-free survival was significantly longer with TTFields/GnP vs GnP (median 15.2 [95% CI: 10.3, 22.8] vs 9.1 months [95% CI: 7.4, 12.7]; HR 0.74 [95% CI: 0.56, 0.97], p=0.027). Post-hoc analysis showed significant distant PFS benefit (median 13.9 [95% CI: 12.2, 16.8] vs 11.5 months [95% CI: 10.4, 12.9], HR 0.74 [95% CI: 0.57, 0.96], p=0.022) with TTFields/GnP vs GnP. ORR was similar between arms (36.1% [95% CI: 30.0, 42.4] vs 30.0% [95% CI: 24.3, 36.2], p=0.094). 97.8% and 98.9% of patients who received TTFields/GnP and GnP, respectively, had adverse events (AEs) and 88.6% and 84.3% had grade ≥3 AEs. The most frequent grade ≥3 AEs were neutropenia (47.8% and 47.6%) and anemia (21.9% and 22.3). 81% of patients receiving TTFields/GnP had device-related AEs, mostly grade 1/2 skin AEs, e.g., dermatitis (27.7%), rash (17.5%), and pruritus (15.0%); grade 3 and grade 4 device-related AEs occurred in 9.1% and 0.4% of patients, respectively. Conclusions: PANOVA-3 is the largest phase 3 trial exclusively performed in patients with LA-PAC and the first to show a statistically significant OS benefit. With no additive systemic toxicity and a statistically significant pain-free survival benefit, TTFields therapy is a potential new standard treatment for LA-PAC. Clinical trial information: NCT03377491 .

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

TPS3160 Background: Patients (pts) with recurrent or metastatic solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), gastric adenocarcinoma (GC), and pancreatic ductal adenocarcinoma (PDAC), have limited treatment options with short PFS and OS despite recent advances (1-3). Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is highly expressed across multiple solid tumors, such as CRC, GC, PDAC, and NSCLC. Restricted normal tissue expression and efficient lysosomal trafficking of CEACAM5 highlight its potential as an anticancer target. SGN-CEACAM5C is a novel investigational antibody-drug conjugate (ADC) directed to CEACAM5 composed of the humanized immunoglobulin G (IgG1) anti-CEACAM5 monoclonal antibody tusamitamab chemically conjugated to 8 molecules of the topoisomerase 1 inhibitor 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT). SGN-CEACAM5C selectively binds to CEACAM5 present on the cell surface and is internalized via the endo-lysosomal pathway, with subsequent release of the payload through enzymatic cleavage. Release of the cytotoxic payload induces DNA damage, cell cycle arrest in S phase, and apoptosis in tumor cells. In vitro bystander activity was observed against tumor cells without CEACAM5 surface expression. SGN-CEACAM5C is highly active in multiple patient-derived xenograft models, including CRC, GC, and NSCLC, across various levels of CEACAM5 expression (4,5). These preclinical findings justify evaluation of SGN-CEACAM5C in a clinical trial setting. Methods: SGNCEA5C-001 (NCT06131840) is a phase 1, open-label, multicenter study designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of SGN-CEACAM5C in adults with select advanced solid tumors. This study consists of dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion (Part C). Eligible pts are adults ≥18 years of age with confirmed metastatic or unresectable solid tumor malignancy, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, an ECOG PS of 0-1, and 1 of the following tumor types: CRC, GC/gastroesophageal junction adenocarcinoma (GEJ), PDAC, NSCLC (squamous/non-squamous), or SCLC. Primary endpoints include incidence of AEs, laboratory abnormalities, dose modifications due to AEs, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of PK parameters, incidence of antidrug antibodies, objective response rate and best response per RECIST v1.1 by investigator, duration of response, PFS, and OS. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Recruitment is ongoing for Part A in North America. 1. Bordry 2021. 2. Chakrabarti 2022. 3. Merle 2022. 4. Baudat 2023. 5. Baudat 2024. Clinical trial information: NCT06131840 .

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

A woman in her 50s previously treated for early-stage breast cancer, parotid mucoepidermoid carcinoma and Caroli’s disease was diagnosed with stage IV pancreatic ductal adenocarcinoma (PDAC) metastatic to the liver and was found to harbour a BRCA1 germline mutation. She had palliative chemotherapy, initially with 5-fluorouracil, leucovorin, irinotecan and oxaliplatin, and then FOLFIRI and capecitabine, achieving a sustained near-complete response for at least 86 months. Chemotherapy was eventually discontinued when she was diagnosed with a tongue squamous cell carcinoma. Despite withholding systemic therapy, she has maintained a durable response. This is the first report in the English literature showing a sustained duration of response in a patient with PDAC and BRCA1 germline mutation.

408 Background: Standard of care for CCA/GBC is C-G therapy. MAbs (ATZ, pembrolizumab) targeting PD-L1 show promise in treating CCA/GBC. Hyaluronan (HA), which may impede drug and immune cell access, is high (67%) in CCA/GBC tumors. PEGPH20 enzymatically degrades HA. HALO 110-101 (NCT03267940) evaluates safety and activity of PEG-C-G-ATZ or PEG-C-G versus C-G in CCA/GBC pts. Methods: This study comprises two parts. In Run-In (RI) six pts were enrolled in PEG-C-G arm, then six pts in PEG-C-G-ATZ arm. Eight additional pts may be enrolled for tolerability. In Expansion (EX), up to 50 pts will be enrolled for efficacy. Treatment (Tx) cycle is 21 days (d). PEGPH20 dose is 3 μg/kg on d1, eight and 15 and ATZ dose is 1200 mg (one–three hours after PEGPH20) on d1 (PEG-C-G-ATZ only). C-G is dosed at 25 mg/m2 C and 1000 mg/m2 G on d2 and nine. In C-G arm (EX only), C-G is dosed on d1 and 8. Primary endpoints are ORR (RECIST v1.1), AEs (NCI CTCAE v4.03), laboratory/safety (RI only); secondary endpoints are PK; DOR, DCR, PFS; OS, OS by PD-L1 expression; ORR and DOR (imRECIST). Results: Eighteen pts have been enrolled (nine in each arm). The mean (SD) age is 57 (12.2) yrs in PEG-C-G and 69 (8.8) yrs in PEG-C-G-ATZ. 56% were men. All pts experienced ≥ 1 AE. The most common AEs are nausea, fatigue (50% each); decreased appetite (44%); anemia, constipation (39% each); thrombocytopenia, oedema peripheral, AST increased, myalgia (33% each). To date, there has been one dose-limiting toxicity (febrile neutropenia) in the PEG-C-G arm. There have been no deaths due to AEs. Conclusions: The overall safety profile of PEGPH20 + C + G ± ATZ is acceptable and consistent with safety observed for the individual components. There were no DLTs resulting in a dose reduction of PEGPH20, which is being dosed at 3 μg/kg in the EX phase. Clinical trial information: NCT03267940. [Table: see text]

TPS543 Background: Cholangiocarcinoma (CCA) is treated with CIS and GEM (CISGEM), but prognosis is poor. Hyaluronan (HA) accumulation in solid tumors may impede drug and immune cell access. PEGPH20 targets tumors that accumulate HA (HA-high). This study (NCT03267940) plans to enroll 70 subjects to evaluate the safety and activity of PEGPH20 + programmed cell death-ligand 1 (PD-L1) agent atezolizumab, (PEGCISGEMATEZO), & PEGPH20 + CISGEM (PEGCISGEM) in HA-high subjects with CCA and gallbladder cancer. Study will comprise initial run-in and expansion portions. Primary endpoints include incidence of AEs and other laboratory/safety parameters and ORR (RECIST v1.1). Secondary endpoints include PK parameters; DOR, DCR, PFS, and ORR (RECIST v1.1 and immune-modified RECIST); and OS and OS by PD-L1 expression. Methods: ~6 HA-high subjects will be enrolled in PEGCISGEM arm run-in portion and undergo at ≥1 cycle; subsequently, 6 HA-high subjects will enter the PEGCISGEMATEZO arm. Treatment period will be 21-day cycles. In the expansion portion, ~50 HA-high subjects will be enrolled and randomized in a 2:2:1 ratio into PEGCISGEMATEZO, PEGCISGEM, and CISGEM arms. PEGPH20 is planned to be administered at 3.0 μg/kg on Days 1, 8 and 15 of all cycles in both portions. ATEZO will be administered at 1200 mg 1–3 hours after PEGPH20 on Day 1 of each 21-day cycle in the PEGCISGEMATEZO arm in both portions. In the PEGCISGEM & PEGCISGEMATEZO arms, dosing schedule for CISGEM is the same during both portions, with administration of 25 mg/m2 CIS and 1000 mg/m2 GEM on Days 2 and 9 of each cycle. In CISGEM control arm (expansion only), dosing schedule will be on Days 1 and 8 of each cycle. Treatment will continue until death, withdrawal of consent, disease progression, or unacceptable toxicity. Tumor response will be evaluated using RECIST v1.1. AEs will be graded per NCI CTCAE v4.03. Tumor samples will be tested retrospectively for PD-L1 expression. Safety data will be periodically monitored by an independent data monitoring committee. Clinical trial information: NCT03267940.

Abstract Lessons Learned OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation that exhibited promising anticancer activity in preclinical models. In this first-in-human phase I study of OPB-111077 in unselected advanced cancers, treatment-emergent adverse events, most frequently nausea, fatigue, and vomiting, were generally mild to moderate in intensity and could be medically managed. Overall, only modest clinical activity was observed after OPB-111077 given as monotherapy. Notable antitumor activity was seen in a subject with diffuse large B-cell lymphoma. Background OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation with promising anticancer activity in preclinical models. Methods Open-label, phase I trial of OPB-111077 in advanced cancers with no available therapy of documented benefit. Initial dose escalation in unselected subjects was followed by dose expansion. Patients received oral OPB-111077 daily in 28-day cycles until loss of clinical benefit. Results Eighteen subjects enrolled in dose escalation, and 127 in dose expansion. Dose-limiting toxicities were observed at 300 mg and 400 mg QD; maximum tolerated dose was defined as 250 mg QD. Frequently reported treatment-emergent adverse events (TEAEs) included nausea, fatigue, and vomiting. TEAEs were generally mild to moderate and could be medically managed. OPB-111077 reached micromolar drug concentrations, had an elimination half-life of approximately 1 day, and reached steady-state by day 8. A durable partial response was observed in one subject with diffuse large B-cell lymphoma. Seven subjects with diverse tumor types had stable disease or minor responses for at least eight treatment cycles (224 days). Conclusion OPB-111077 is generally well tolerated, and its pharmacokinetic profile is sufficient for further clinical development. Notable clinical activity was observed in a subject with diffuse large B-cell lymphoma. Overall, modest efficacy was observed against unselected tumors.

Abstract Background: OPB-111077 is a new chemical entity with anticancer activity in vitro and in human tumor xenograft models. The compound modulates STAT3 phosphorylation but has no marked effect on activity of any of 69 tested human tyrosine or serine/threonine kinases. This P1 study evaluated safety, pharmacokinetics, and antitumor activity of OPB-111077 in subjects with advanced cancers. Methods: Primary objectives determined safety, tolerability, and maximum tolerated dose (MTD) of OPB-111077 given orally once daily to subjects with advanced cancer. Secondary objectives included pharmacokinetics (PK) and antitumor activity. In the first 2 cycles of dose escalation, Day 1 dose was followed by 2 days off study therapy for PK. The starting dose was 100 mg once daily. Single subject cohorts with dose level doublings were studied until the first ≥ Grade 2 AE that was possibly drug-related. Then a 3+3 design was used. After MTD determination, expansion cohorts were opened for subjects with malignancies possibly susceptible to inhibition by OPB-111077, including breast, cervical, colorectal, gastric, kidney, myeloma, non-small cell lung, non-Hodgkin's lymphoma, ovarian, and prostate cancers, as well as “rare tumors” for which STAT3 inhibition might generate clinical activity. Results: Overall 145 subjects received OPB-111077. Mean age was 61 years (range 21-88), and 51% of subjects were female. Dose escalation occurred in 18 subjects. Four DLTs were observed: 2 at 400 mg QD (G3 nausea/vomiting), and 2 at 300 mg QD (G3 vertigo and G3 nausea/vomiting). The MTD was 250 mg QD. All subjects recovered from DLTs after drug discontinuation. Adverse events (AEs) that may be attributable to OPB-111077 include nausea (71%), vomiting (46%), fatigue (44%), dizziness/vertigo (26%), and hypothyroidism (19%). Most AEs were CTCAE Grades 1 or 2 and manageable with supportive treatment. OPB-111077 exposures increase dose proportionally and linearly with increasing single and multiple doses up to 250 mg. Median time to peak plasma concentration (tmax) is about 4 hours. Mean maximum plasma concentration (Cmax) is 16 μmol/L and mean trough concentration is 6 μmol/L after multiple doses of 250 mg QD. Terminal half-life is about 23 hours and steady state was reached by about 1 week. The major metabolites in plasma are pharmacologically inactive and unlikely to contribute to efficacy. Administration with a high fat meal did not significantly alter OPB-111077 bioavailability. Expansion cohorts enrolled 127 subjects, including NSCLC (13), breast (13), ovarian (11), kidney (11), colorectal (10), prostate (8), lymphoma (8), gastric (7), cervical (3) cancers, and myeloma (1). Rare tumors with STAT rationale included sarcomas (13), neuroendocrine tumors (7), squamous cell carcinomas (5), other carcinomas (12), and other malignant tumors (5). One RECIST Partial Response occurred in a subject with Diffuse Large B Cell Lymphoma. In addition, 7 subjects with had stable disease for at least 8 treatment cycles, including gastric (2), cholangiocarcinoma, kidney, prostate, K-Ras mutant colon cancer, and esthesioneuroblastoma. Conclusions: OPB-111077 can be given safely and achieves clinically active drug levels in humans. Single agent clinical activity was observed. Translational work is ongoing to determine factors driving clinical activity Citation Format: Gregory Cote, Kyriakos Papadopoulos, Amita Patnaik, Drew Rascoe, Lon Smith, Andrea Bullock, Keith Flaherty, Geoffrey Shapiro, Jordan Berlin, Manish Monga, Thomas Habermann, Thomas Witzig, Chester Lin, Lin-Feng Tsai, Agnes Elekes, Naoto Ohi, Kunihiko Tatsumi, Anthony Tolcher. A phase 1, open-label multiple dose escalation trial to determine safety and tolerability of once daily OPB-111077 in subjects with advanced cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B118.